Ocular therapeutic system manufactured from copolymer

ABSTRACT

Drug-delivery device for releasing a drug at a continuous and controlled rate for a prolonged period of time is comprised of a shaped body of polymeric material containing a pharmaceutically acceptable drug and permeable to passage of the drug by diffusion. The polymeric material is an ethylene-vinyl acetate copolymer having a vinyl acetate content of about 4 to 80% by weight and a melt index of about 0.1 to 1000 grams per 10 minutes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.582,353 filed on May 5, 1975 which application is a division of U.S.patent application Ser. No. 281,446 filed on Aug. 17, 1972, now U.S.Pat. No. 3,903,880, which application is a continuation-in-part of U.S.patent application Ser. No. 80,531, filed on Oct. 14, 1970 and nowabandoned. These applications are assigned to the same assignee of thisapplication and benefit of their filing dates is claimed.

BACKGROUND OF THE INVENTION

This invention relates to a novel and useful drug-delivery device forreleasing a pharmaceutically acceptable drug at a controlled andcontinuous rate for a prolonged period of time to produce aphysiological or pharmacological effect. The drug delivery device iscomprised of a drug release rate controlling polymeric materialsurrounding at least a part of the drug or the material contains thedrug therein. The material is permeable to the passage of drug bydiffusion.

Often, in therapeutic, medical and veterinary programs, it is desirableand important to provide for the slow release of a drug to the body at acontrolled rate over a prolonged period of time. In many therapeuticprograms such a rate of release should be constant or have a zero ordertime dependence, that is, the rate of release is independent of time.For example, in contraception, it has been found that fertility can beregulated by release of progesterone to the uterus from a drug-deliverydevice inserted in the uterine lumen; with release of progesterone at aconstant rate for a prolonged period, a convenient long term birthcontrol procedure is provided. Similary, glaucoma can be controlled byrelease of pilocarpine from a thin film drug-delivery device insertedbeneath the lower eyelid. Here too, the active beneficial agent shouldbe released at a constant rate.

Different approaches have heretofore been tried to obtain adrug-delivery device for releasing drug at a conrolled rate. Oneapproach, which has received great attention, is to mix the drug with acarrier material that is gradually broken down by body fluids, the drugbeing released as the carrier disintegrates. Numerous carriers have beenused in such systems including waxes, oils, fats, soluble polymers andthe like. While some of these systems have provided for a delayedrelease of the drug, constant release rate has not been obtained. Onereason for this is that as the carrier disintegrates the surface area ofthe dosage unit decreases, concomitantly exposing increasingly smallerquantities of the carrier to the surrounding body fluids. Thisinherently results in a decline in the release rate over time. Moreover,there has been little success in gaining control over drug release rateby this approach.

Another approach has been to enclose the drug within a capsule havingpolymeric walls through which the drug can pass by diffusion. Anapproach of this kind is set forth in U.S. Pat. No. 3,279,996. Thesedevices too have inherent difficulties. These prior systems havegenerally been based on the use of silicone rubber polymers, especiallypolydimethylsiloxanes, as the diffusion control membrane. In large part,these silicone polymers were selected because of their high permeabilityto some important drug molecules. But it has now been found that thishigh permeability can be a significant disadvantage which defeats theprimary objective of an acceptable and useful drug-delivery device.Thus, with many important drug molecules, such as progesterone, thediffusion rate through polydimethylsiloxane membranes is very great,often greater than the rate of clearance of the diffused drug from theouter surface of the capsule. In many instances, this results in therate limiting step being clearance of the drug from the exterior of thecapsule, rather than diffusion through the capsule wall. Clearance ratewithin the body is difficult to control, as it is subject to frequentchanges and, when it is the rate-limiting step, the objective ofproviding a drug-delivery device which releases drug at a constant rateover time cannot be obtained. Also, silicone rubbers have a tendency toabsorb lipoidal materials from the body. When this effect occurs invivo, the nature of the membrane changes, altering the release rate.Still another problem with the silicone rubber dosage forms is thedifficulty encountered in fabrication, attributable largely to thesilicone rubber itself, that is, it is not thermoplastic and accordinglyit does not lend itself to the manufacture of heat selaed drug deliverydevices. While the above mentioned polymer, silicone, has been found tohave too high a permeability to many therapeutic drugs to lend itself tosuccessful use as a drug release rate controlling barrier, in otherinstances, polymers such as poly(ethylene), which is thermoplastic andhas a high degree of crystallinity, has also been found to have too higha melting point that can adversely affect the drug during fabrication ofthe device, and because of its crystallinity has too low a permeabilityto drug to be successfully used as a drug release rate barrier.

In unrelated, non-therapeutic fields, various other polymeric materialshave been used for releasing active substances. For example, a closedcontainer whose walls are comprised of ethylene vinyl acetate copolymeris described in U.S. Pat. No. 3,310,235 as seemingly suitable forreleasing volatile, organic and toxic phosphorous biocides by theprocess of physical evaporation. With these containers, all biociderelease is achieved by evaporation from the surface, and if theingredient is not sufficiently volatile at the use temperature thecontainer has no apparent practical value. Evaporation is preferablyachieved by using a woven cloth which acts as an evaporation surface.However, release rate by evaporation is difficult to regulate andvirtually impossible to control as it is subjected to uncontrollableenvironmental conditions, the vapor pressure of the substance, and thedegree of saturation of the volatile substance in the environment. Thetype of clearance inherently defeats the basic purpose of providing adrug delivery device which releases a drug at a controlled rate for aprolonged period of time such as by the process of diffusion.

It is also known to the art to use polymeric materials such asethylene-vinyl acetate copolymer in other forms and for differentpurposes. For example, in Great Britain Pat. No. 1,126,849 there isdisclosed a cellular polymer in which open cells are purposely formedfor the movement of gases into these pores. These cellular polymers aredisclosed to have non-medical uses and generally these polymers do notlend themselves to use as diffusional drug devices. In U.S. Pat. No.3,400,011 polymeric materials are mixed with waxes and used for coatingingredients that are subsequently released by the osmotic movement ofexternal fluids into the coating causing it to rupture and release thesurrounded ingredient. In U.S. Pat. No. 3,618,604 there is disclosed anocular drug delivery device that represents a substantial improvementover previously proposed drug devices and which devices can besuccessfully used for their intended purpose in the management of ocularmedicine. But, the use of some of the materials set forth therein, forexample, partially hydrolyzed polyvinylacetate because of its gel likeproperties, has led to manufacturing difficulties and also has not giventhe desired drug release rates in many instances. Other incidental andnon-therapeutic uses for vinyl acetate copolymers are disclosed inFrench Patent 1,489,490 as a thickner and in French Patent 1,505,267 asa non-diffusional formless base for chewing gum.

SUMMARY OF THE INVENTION

One important object of this invention is to provide a novel and usefulshaped drug-delivery device for prolongedly releasing drug at acontrolled rate, by providing a material that has the ability to giventherapeutically operable drug release rates in vivo, whilesimultaneously remaining substantially free of any adverse unwantedtoxic effects to the host.

Still another object of this invention is to provide a medical andveterinary useful drug-delivery device which can release drug at a ratewhich does no vary with time.

One further object of this invention is to provide an intrauterine,shaped memory retaining device for controlling fertility over a longperiod of time.

Yet a further object of this invention is to provide a drug deliverydevice fabricated from a material which is compatible with body tissueand exhibits a low toxicity thereto.

Still yet another object of the invention is to provide a reliable andeasily used drug delivery device for continuously administeredcontrolled quantities of drug to the body or to a drug receptor site.

Still a further and immediate object of this invention is to provide adrug delivery device for the administration of a locally acting orsystemically acting drug to produce a physiologic or pharmacologiceffect.

Still another object of the invention is to provide a drug deliverydevice made from a material that can be fabricated, e.g., heat sealed,without substantially adversely effecting the properties of the drugcontained therein.

Yet a further object of the invention is to provide a drug deliverydevice formed of a drug release rate controlling material permeable tothe passage of drug by diffusion which process is the drug release ratecontrolling for the drug delivery device.

In accomplishing the objects of this invention, one feature resides in adrug-delivery device for releasing drugs over a prolonged period of timecomprising a drug reservoir and a polymeric barrier through which thedrug passed by diffusion. The polymeric barrier is an ethylene-vinylacetate copolymer having a vinyl acetate content of about 4 to 80% byweight and a melt index of about 0.1 to 1000 grams per ten minutes.

Another feature of this invention resides in a drug dosage form forreleasing drug at a predetermined rate over a prolonged period of timecomprising a body of polymeric material containing a drug, the polymericbody being permeable to passage of the drug by diffusion and beingcomprised of an ethylene-vinyl acetate copolymer having a vinyl acetatecontent of about 4 to 80% by weight and a melt index of about 0.1 to1000 grams per ten minutes.

Still another feature of this invention resides in a new and useful drugdelivery device for insertion in the uterine lumen through the cervix,the device comprising a biologically acceptable body of polymericmaterial containing a progestational agent, the polymeric body beingpermeable to passage of the progestational agent at a fertilitycontrolling rate by diffusion and being comprised of an ethylene-vinylacetate copolymer having a vinyl acetate content of about 4 to 80% byweight and a melt index of about 0.1 to 1000 grams per ten minutes.

Yet a further feature of this invention resides in an eye medicationdispensing device which is a flexible body of an ethylene-vinyl acetatecopolymer having a vinyl acetate content of about 4 to 80% by weight anda melt index of about 0.1 to 1000 grams per ten minutes.

The device contains an ophthalmic drug which is dispensed to the eye bydiffusion through the copolymer. The device is adapted for insertion inthe cul-de-sac of the conjunctiva between the sclera of the eyeball andthe lid, to be held in place against the eyeball by the pressure of thelid.

Yet a further feature of this invention resides in a drug dispensingdevice which is comprised of a flexible body of an ethylene vinylacetate copolymer having a vinyl acetate content of about 4 to 80% byweight and a melt index of about 0.1 to 1000 grams per ten minutes. Thedevice contains a drug which is released from the device by diffusionthrough the copolymer to the vagina, bladder or other body cavity.

Other objects, features and advantages of this invention will becomemore apparent to those skilled in the art from the following detaileddescription of the invention, taken in conjunction with the drawings,and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but rather are set forthto illustrate various embodiments of the invention and wherein likereference numerals designate like parts, the drawings are as follows:

FIG. 1 is a side cross-sectional view of a drug-delivery device of theinvention;

FIG. 2 is a side cross-sectional view of another embodiment of thedrug-delivery device of the invention;

FIG. 3 is a side cross-sectional view of still another embodiment of theinvention in the form of an adhesive patch;

FIG. 4 is a front view, partially in cross-section, of the drug-deliverydevice of the invention in the form of a drug dispensing intrauterinedevice; and

FIG. 5 is a side view, partially in cross-section, of the device of theinvention in the form of an eye medication dispensing device.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with this invention, it has now been unexpectedly foundthat ethylene-vinyl acetate copolymers can be successfully manufacturedinto novel and useful drug delivery devices and can therefore be usedfor the controlled release of drugs by diffusion.

As illustrated in FIG. 1, the novel and useful drug-delivery device 10of the invention can have a wall 11 fabricated of ethylene-vinyl acetatecopolymer enclosing a reservoir 12a containing a drug 12. Drug 12 is onecapable of diffusing through ethylene-vinyl acetate copolymer walls 11.Alternatively, as illustrated in FIG. 2, the drug-delivery device 10 canbe comprised of a solid matrix 11 of ethylene-vinyl acetate copolymer,which also serves as a drug reservoir, having drug 12 distributedtherethrough.

Essential to this invention is the use of an ethylene-vinyl acetatecopolymer as the rate limiting barrier for the controlled release ofdrugs by diffusion. This requires that the drug-delivery device have atleast one barrier or wall of biologically acceptable ethylene-vinylacetate copolymer through which the drug will pass by diffusion. Variousforms of the invention are included within this framework. Thus, thedevice of the invention can have a single ethylene-vinyl acetatecopolymer membrane on one surface thereof and through which the drugwill pass by diffusion. One form of this embodiment is illustrated inFIG. 3, a detailed description of which is presented later in thespecification. In another embodiment of the invention, the device is abiologically acceptable container, with walls of ethylene-vinyl acetatecopolymer, and the drug in the interior thereof; see FIG. 1 for example.In this form of the invention, drug alone can be within the interiorreservoir of the device or the drug can be dispersed in a liquid,semi-solid, or solid matrix and the matrix enclosed within theethylene-vinyl acetate copolymer barrier. In each of these embodiments,passage of the drug diffusion through the ethylene-vinyl acetatecopolymer is the rate controlling step for drug administration. Forfurther details of such a drug-delivery device in which the drug isdispersed throughout a solid matrix enclosed within a barrier throughwhich drug can pass by diffusion, reference is made to copendingapplication Ser. No. 42,786, filed June 2, 1970 and now U.S. Pat. No.3,854,480 issued on Dec. 17, 1974 for an invention of AlejandroZaffaroni assigned to the assignee of this invention. The disclosure ofthat co-pending Application is relied upon and incorporated herein byreference. In another embodiment of the invention (as in FIG. 2), thedrug 12 is distributed throughout a matrix, which matrix in thisembodiment is reservoir 12a, of ethylene-vinyl acetate copolymer 11.Preferably, solid particles or a liquid form of the drug are used,although the drug can be in solution in the polymeric matrix.

Drug-delivery devices of the invention can take a wide variety of shapesand forms for administering the drugs at controlled rates to differentareas of the body. Thus, the invention includes external and internaldrug-delivery devices such as skin patches, shape retaining buccalpatches, sublingual or shaped buccal tablets, peroral dosage forms,implantates for releasing a drug in the tissues of a living organism,pessaries, prosthesis, artificial glands, vaginal or rectalsuppositories, cervical rings as described in Belgian Patent No.726,454, troches, drug-dispensing intrauterine devices, ocular insertsas described in U.S. Pat. No. 3,416,530, and preshaped drug deliverydevices for administering a drug in a body cavity. In each instance, thedrug-delivery device has an ethylene-vinyl acetate copolymer barrier forrelease of the drug by diffusion at a controlled rate and it is ofappropriate known shape for implantation in the desired body tissues,cavities or the like, respectively, or for application to a particularbody internal or external area.

For example, as illustrated in FIG. 3, the drug-delivery device 10 ofthe invention can be comprised of a film 11 of ethylene-vinyl acetatecopolymer on one face surface of a reservoir 12a containing drug 12. Thereservoir is bounded by side walls 13 and top surface wall 14 all ofwhich preferably are impermeable to passage of drug 12. About theperimeter of film 11 is a coating of a pressure-sensitive adhesive 15.This drug-delivery device is especially adapted to apply drug to theskin or buccal mucosa by diffusion through film 11 at a predeterminedrate.

One especially important use of the invention is in drug dispensingintrauterine devices for controlling fertility. The reason for this isthat it has unexpectedly been found that ethylene-vinyl acetatecopolymers provide excellent diffusion barriers for the controlledrelease of progestational agents, such as progesterone, over a prolongedperiod of time. Such devices incorporate within their interior aprogestational agent, such as progesterone, which is released bydiffusion through the ethylene-vinyl acetate copolymer walls of thedevice. The intrauterine contraceptive device is of appropriate shapefor comfortable insertion and retention in the uterus. For example, thedevice can be in the form of a Lippe's Loop in U.S. Pat. No. 3,250,271,Shamrock in U.S. Pat. No. 3,077,879, Birnberg Bow in U.S. Pat. No.3,319,625, and the like. As illustrated in FIG. 4, the drug-deliverydevice 10 of the invention is in the form of an acceptable intrauterinedevice which in use is disposed within lumen 16 of a uterusschematically represented as being defined by sidewalls 17, top wall 18,and cervix 19. By slow diffusion of an anti-fertility agent such as aprogestational agent through the ethylene-vinyl acetate copolymer wallsof the intrauterine device, fertility can be controlled for long periodsof time, for example up to one year or longer.

FIG. 5 illustrates another important use of the invention, in eyemedication dispensing devices. Such devices are flexible bodies ofethylene-vinyl acetate copolymer containing an ophthalmic drug, such aspilocarpine, which is dispensed to the eye by diffusion through thecopolymer. The device is adapted for insertion in the cul-de-sac of theconjunctiva between the sclera of the eyeball and the lid, to be held inplace against the eyeball by the pressure of the lid. As illustrated inFIG. 5, the device 10 of the invention can have ethylene-vinyl acetatecopolymer walls 11 surrounding a reservoir 12a containing an ophthalmicdrug 12. In use, drug 12 is dispensed to eyeball 20 by diffusion throughethylene-vinyl acetate copolymer walls 11. Device 10 is illustrated asbeing placed in lower cul-de-sac 21 of the conjunctiva between thesclera of the eyeball and the lower lid 22. Alternatively, device 10 canbe placed in upper cul-de-sac 23 of the conjunctiva between the scleraof the eyeball and the upper eyelid 24. In either case, it is held inplace against the eyeball by the pressure of the lid. For furtherdetails on these eye medication dispensing devices, reference is made toU.S. Pat. No. 3,416,530 and co-pending patent application Ser. No.831,761 filed June 9, 1969 now U.S. Pat. No. 3,618,604, and assigned tothe assignee of this invention. The disclosure of that co-pendingapplication is relied upon and incorporated herein by reference. Oneimportant advantage in using ethylene-vinyl acetate copolymers in sucheye medication dispensing devices is that precise control over the rateof release of ophthalmic drugs, especially pilocarpine, is obtained,with the drug being released at a therapeutically effective rate.

Ethylene-vinyl acetate copolymers are well known commercially availablematerials. Exemplary techniques for their preparation are described inU.S. Pat. Nos. 2,200,429 and 2,396,785. In its broadest aspects, thepresent invention contemplates use of ethylene-vinyl acetate copolymershaving a vinyl acetate content of about 4 to 80% by weight of the totaland a melt index of about 0.1 to 1000 grams per ten minutes. Melt indexis the number of grams of polymer which can be forced through a standardcylindrical orifice under a standard pressure at a standard temperatureand thus is inversely related to a molecular weight. As used in thisspecification and the appended clams, melt index is as determined inaccordance with standard ASTM D 1238-65T condition E practice.Preferably, the ethylene-vinyl acetate copolymer has a vinyl acetatecontent of about 4 to 50% by weight, a melt index of about 0.5 to 250grams per ten minutes, a density having a range of about 0.920 to 0.980,and a frequency of acetoxy groups on the polyethylene backbond of 1/150to 1/8. More preferably, the polymer has a vinyl acetate content of 4 to40% by weight and a melt index of about 0.5 to 25 grams per ten minutes.Moreover, it has been surprisingly found that the absolute release rateof drug through the ethylenevinyl acetate copolymer barrier can bevaried and accurately controlled by selecting a copolymer having thefrequency of acetoxy group with the range set forth above.

The ethylene-vinyl acetate copolymer, which acts as the rate controllingbarrier, is permeable to drugs, to permit passage of the drug bydiffusion through the polymer at a relatively low rate. Normally, therate of passage of the drug through the polymer is dependent on thesolubility of the drug therein, as well as on the thickness of thepolymeric barrier. This means that selection of particularethylene-vinyl acetate copolymer compositions will be dependent on theparticular drug to be used. By varying the composition and thickness ofthe rate controlling barrier, the dosage rate per area of the device canbe controlled; for the ethylene-vinyl acetate copolymer acts to meterthe flow or diffusion of drug to the exterior of the device. Thus,devices of the same surfaces area can provide different dosage of a drugby varying the characteristics of the ethylene-vinyl acetate copolymer.

In addition to varying the percentage of vinyl acetate in the copolymerand the melt index or molecular weight, the properties of the copolymercan be changed by selectively hydrolyzing its acetate groups to alcoholgroups. By converting a portion of the vinyl acetate units of thepolymer to vinyl alcohol units, the polymer is rendered more hydrophilicand the rate of passage of relatively hydrophilic drug molecules isincreased. The percentage of vinyl acetate units hydrolyzed to vinylalcohol units can vary widely but typically from about 20 to 60% areconverted. This partial hydrolysis is a well known procedure and can beaccomplished under standard conditions well known in themselves.Exemplary hydrolysis procedures are set forth in U.S. Pat. Nos.2,386,347; 2,399,653; 3,386,978; 3,494,908, and the like.

Permeability of the copolymer of drugs by diffusion also can be variedby incorporating fillers into the copolymer. Typical fillers that can beemployed in practice of the invention are silica, clay, barytes, carbonblack, lithopone, zinc oxide, etc. It should be realized that use ofmany of these fillers will affect the melt index of the copolymer.However, when melt index is used herein to define the copolymer it isused as a measure of molecular weight and refers to the melt index ofthe particular copolymer composition without any filler present.Additionally, in those instances where the rate of release of drug isless than a preselected rate, the drug can be converted to knownderivatives that have a greater permeability of drug through themembrane to increase the rate of release. Also, where the rate of drugdiffusion is too slow, the rate can easily be increased by using drugdelivery devices as embodied in FIG. 2.

Selection of the particular ethylene-vinyl acetate copolymer is governedin large part by the drug to be incorporated in the device, as well asby the desired rate of release of the drug. Those skilled in the art canreadily determine the rate of diffusion of drugs through thesecopolymers and select suitable combinations of copolymer and drug forparticular applications. Various techniques can be used to determine thepermeability of the copolymers to different drugs. One that has beenfound to be eminently well suited is to cast or hot press a film of thecopolymer to a thickness in the range of 2 to 60 mils. The film is usedas a barrier between a rapidly stirred (e.g. 150 r.p.m.) saturatedsolution of the drug and a rapidly stirred solvent bath, both maintainedat constant temperature (typically 37° C). Samples are periodicallywithdrawn from the solvent bath and analyzed for drug concentration. Byplotting drug concentration in the solvent bath versus time, thepermeability constant P of the film is determined by the Fick's FirstLaw of Diffusion.

    Slope of plot = (Q.sub.1 -Q.sub.2)/(t.sub.1 - t.sub.2) = P (AC/h)

wherein

Q₁ = cumulative amount of drug in solvent in micrograms at t₁

Q₂ = cumulative amount of drug in solvent in micrograms at t₂

t₁ = elapsed time to first sample, i.e., Q₁

t₂ = elapsed time to second sample, i.e., Q₂

a = area of film in cm²

C = initial concentration of drug in saturated solution at t

h = thickness of film in cm By determining the slope of the plot, i.e.,(Q₁ - Q₂)/t₁ - t₂) and solving the equation using the known or measuredvalues of A, C, and h, the permeability P constant in cm² /time of thefilm for a given drug is readily determined. Of course, thispermeability constant is an inherent characteristic of a copolymer ofparticular composition and melt index and is unchanged whether thematerial is used as a matrix or as a film wall. The procedures used todetermined the rate of drug release through the ethylene-vinyl acetatecopolymer can easily be ascertained by standard techniques known to theart as recorded in J. Pharm. Sci., Vol. 52, pages 1145 to 1149, 1963;ibid Vol. 53, pages 798 to 802, 1964; ibid Vol. 54, pages 1459 to 1464,1965; ibid Vol. 55, page 840 to 843 and 1224 to 1239, 1966; Encyl.Polymer. Sci. Technol., Vol. 5 and 9, pages 65 to 82 and 794 to 807,1968; the references cited therein, and the like.

The rate of solubilization, or the rate at which drug will go intosolution or dissolve in a vehicle confined within the reservoir isquantitatively governed by known physico-chemical principles. For anexample, a drug particle dispersed in a vehicle is surrounded by a thinlayer of vehicle having a finite thickness l in cm. This layer isconsidered as an integral part of the drug and it is characteristicallyreferred to as the "stagnant layer." The stagnant layer remains a partof the surface of the drug, moving wherever the drug moves. Using Fick'sFirst Law of Diffusion, the rate of solution is the rate at which adissolved drug diffuses through the stagnant layer for supplying drug tothe drug device's reservoir's inner wall. The driving force behind themovement of the drug through the stagnant layer is the difference inconcentration of the drug, C₁, in the stagnant layer at the surface ofthe drug and the concentration C₂ on the farthest side of the stagnantlayer. The difference in concentration C₁ - C₂ determines the rate atwhich drug is solubilized in the vehicle. Hence, if the vehicle on thefarthest side contains its optimum concentration because of a lowrelease by the drug release rate controlling wall, the rate ofsolubilization of new drug will be low. Correspondingly; as drug leavesthe vehicle new drug is solubilized to establish a steady state withinthe vehicle.

The rate of diffusion of a drug in the vehicle comprising the reservoiris broadly determined by measuring the rate of a drug transferred fromone chamber through a sintered glass filter of known pore size andthickness into another chamber and calculating from the obtained datathe drug transfer rate. The method is carried out by adding to a firstconical flask equipped with a ground glass stopper and a stirring bar, ameasured amount of vehicle and simultaneously, the drug in the samevehicle is added to a second conical flask while keeping the level ofthe vehicle in the two flasks the same. Next, the flasks are stirred,and samples drawn at various time intervals for analysis. The measuredrate of drug transport through the sintered glass filter, and theconcentration difference of the drug in the two flasks is thencalculated. These procedures are known to the art in Proc. Roy. Sci.London, Ser. A. Vol. 148, page 1935; J. Pharm. Sci., Vol. 55, pages 1224to 1229, 1966; and references cited therein. The diffusion coefficientof a drug can also be experimentally determined by using the aboveapparatus or similar apparatus and procedures as described in Duffusionin Solids, Liquids and Gases, by W. Jost, Chapter XI, pages 436 to 488,1960, Revised Edition, Academic Press Inc., New York.

The solubility of a drug in the drug release rate controllingethylene-vinyl acetate copolymer material comprising the wall of a drugdelivery device broadly is determined by preparing a satuated solutionof a given drug and ascertaining, by analysis, the amount present in adefinite area of the copolymer material. For example, the solubility ofthe drug in the wall is determined by first equilibrating the wallmaterial with a saturated solution of the drug at a known temperature,for example 37° C, or with a pure liquid drug, if the drug is a liquidat 37° C. Next, drug is desorbed from the saturated wall material with asuitable solvent for the drug. The resultant solution for the drug thenis analyzed by standard techniques such as ultraviolet, visiblespectrophotometry, refractive index, polarography, electricalconductivity and the like, and calculating from the data theconcentration, or solubility of the drug in the material.

The solubility of a drug in a vehicle can be determined by various artknown techniques. One method consists in preparing a vehicle, of thegiven drug and ascertaining by analysis the amount of drug present in adefinite quantity of the vehicle. A simple apparatus for this purposeconsists of a test tube of medium size fastened upright in a water bathmaintained at constant temperature. The vehicle and drug are placed inthe tube and stirred by means of a motor driven rotating glass spiral.After a given period of stirring, a definite weight of the vehicle isanalyzed and the stirring continued for an additional period of time. Ifthe analysis shows no increase of dissolved substance after the secondperiod of stirring, the results are taken as the degree of solubility ofthe drug in the vehicle. Numerous other methods are available for thedetermination of the degree of solubility of a drug in a vehicle.Typical methods used for the measurement of solubility are chemicalanalysis, measurement of density, refractive index, electricalconductivity, and the like. Details of various methods for determiningsolubilities are described in United States Public Health ServiceBulletin No. 67 of the Hygienic Laboratory; Encyclopedia of Science andTechnology, Vol. 12, pages 542 to 556, 1971, published by McGraw-Hill,Inc.; Encyclopaedic Dictionary of Physics, Vol. 6, pages 545 to 557,1962, published by Pergamon Press, Inc; and the like.

Also according to Fick's Law, the rate of drug solution is directlyproportional to the area of the drug, A in cm², as exposed to vehicleand inversely proportional to the length of the path through which thedissolved drug molecule must diffuse. Then, the rate of solution of thedrug is given by

    R = DA/l(C.sub.1 - C.sub.2)

wherein R is the rate of solution, D is a proportionality constantcalled diffusion coefficient in cm² /sec, and C₁, C₂ and l are aspreviously defined. See Remington Pharmaceutical Science, 14the Ed.,pages 246 to 269, 1970, published by Mack Publishing Company.

In practicing the invention, one can employ any drug used to treat thebody and capable of diffusing through an ethylene-vinyl acetatecopolymer at a therapetucially effective rate. Suitable drugs for use intherapy with the drug-delivery device of the invention include, withoutlimitation, drugs that produce a physiologically or pharmacologicallylocalized or systemic effect or effect in mammals including human andprimates, avians such as chicken and turkeys; valuable domestichousehold, sport or farm animals such as horses, dogs, cats, cattle,sheep and the like; or for administering to laboratory animals such asmice, monkeys, rats, guinea pigs; and the like. The active drugs thatcan be adminstered by the novel drug delivery device of the inventioninclude, without limitation:

1. Anti-infectives, such as antibiotics, including penicillin,tetracycline, chloramphenicol, sulfacetamide, sulfamethazine,sulfadiazine, sulfamerazine, sulfamethizole and sulfisoxazole;antivirals, including idoxuridine; and other anti-infectives includingnitrofurazone and the like;

2. Anti-allergenics such as antazoline, methapyrilene, chlorpheniramine,pyrilamine and prophenypridamine;

3. Anti-inflammatories such as hydrocortisone, cortisone, dexamethasone,fluocinolone, triamcinolone, medrysone, prednisolone, and the like;

4. Decongestants such as phenylephrine, naphazoline, andtetrahydrazoline;

5. Miotics and antichlolinesterases such as pilocarpine, carbachol, andthe like;

6. Mydriatics such as atropine, cyclopentolate, homatorpine,scopolamine, tropicamide, eucatropine and hydroxyamphetamine;

7. Sympathomimetics such as epinephrine;

8. Sedatives and Hypnotics such as chloral, pentabarbital,phenobarbital, secobarbital, codeine, (α-bromoisovaleryl) urea, andcarbromal;

9. Psychic Energizers such as 3-(2-aminopropyl) indole, 3-(2-aminobutyl)indole, and the like;

10. Tranquilizers such as reserpine, chlorpromazine, and thiopropazate;

11. Androgenic steroids such as methyltestosterone and fluoxymesterone;

12. Estrogens such as estrone, 17β-estradiol, ethinyl estradiol, anddiethyl stilbesterol;

13. Progestational agents, including progestogen and progestins, such asprogesterone, 19-nor-progesterone, norethindrone, megestrol,melengestrol, chloromadinone, ethisterone, medroxyprogesterone,norethynodrel and 17α-hydroxy-progesterone;

14. Humoral agents such as the prostaglandins, for example PGE₁, PGE₂,and PGF₂α ;

15. Antipyretics such as aspirin, salicylamide, and the like;

16. Antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine;

17. Anti-malarials such as the 4-aminoquinolines, α-aminoquinolines,chloroquine, and pyrimethamine;

18. Antihistamines such as diphenhydramine, dimenhydrinate,tripelennamine, perphenazine, and chloropenazine;

19. Cardioactive agents such as benzydroflumethiazide, flumethiazide,chlorothiazide, and aminotrate; and

20. Nutritional agents such as essential amino acids and essential fats.Other drugs having the same or different physiological activity as thoserecited above can be employed in drug-delivery devices within the scopeof the present invention.

Drugs, contained in the reservoir, can be in different forms, such asuncharged molecules, components of molecular complex or non-irritating,pharmacologically acceptable derivatives thereof. For simple derivativesof the drugs such as pharmaceutically acceptable ethers, esters, amides,and the like which have desirable retention and release characteristicsbut which are easily hydrolyzed by body pH, enzymes to active forms, andthe like can be employed.

The dosage unit amount for conventional beneficial drugs as set forthherein, in the accompanying disclosure and examples, is also known tothe art in standard reference books such as Remington's PharmaceuticalScience, Fourteenth Edition, Part IV, 1970, published by Mack PublishingCol, Easton, Penn.

The amount of drug incorporated in the drug-delivery device variesdepending on the particular drug, the desired therapeutic effect, andthe time span for which the device provides therapy. Since a variety ofdevices in a variety of sizes and shapes are intended to provide dosageregimes for therapy for variety of maladies, there is not critical upperlimit on the amount of drug incorporated in the device. The lower limittoo will depend on the activity of the drug and the time span of itsrelease from the device. Thus, it is not practical to define a range forthe therapeutically effective amount of drug to be incorporated in orreleased by the device. However, the amount of drug present in thereservoir is generally non-limited and it is an amount equal to orlarger than the amount of drug that on its release from the device iseffective for bringing about the drug's physiological or pharmacologicallocal or systemic effects. For example, the amount of drug present inthe reservoir of a drug-delivery device when the device is used for aperiod of time to achieve local or systemic effect is for various drugs,such as 11-desmethoxyreserpine about 5 to 40 mg in the reservoir; foracetophenazine an amount in the reservoir of 100 to 200 mg; forhydrocortisone about 2 to 10 mg in the reservoir; for progesterone areservoir amount of 6.0 to 300 mg; for pilocarpine a reservoir amount of2 to 10 mg; about 160 to 250 mg of butabarbital in the reservoir; about150 to 170 mg of chlorodiazepoxide; from 0.5 to 0.75 gm of methsuximide;from 0.7 to 1.0 gm of ethosuximide; from 20 to 40 mg of hydrolazine;about 50 to 100 mg of totazoline; and the like. Generally, the drugdelivery devices made according to the invention can contain from about250 nanograms to 5 grams of drug for releasing it at a controlled rateof from about 25 nanograms to about 25 grams of drug or larger amountsper day. Of course, other devices containing different amounts of drugfor use for different time periods such as week, month and year are alsoreadily made by the invention.

It will be appreciated by those versed in the art that the unique drugdelivery device of this invention can provide for the programmeddelivery of drug at a rate of delivery characterized by a zero ordertime dependence for prolonged period of time; and, that the devicetherefore lends itself to administering an effective amount of drugneeded for a therapeutic effect while essentially avoiding the presenceof excessive amount of drug at the needed biological site. By aprolonged period of time is meant, as used herein, periods that embracethe time needed for a fast acting drug to effect its end up to periodsthat embrace the continual, uninterrupted, repititious time of a longterm drug delivery device. For example, the prolonged time can be onehour or more for drugs, like local anesthetics, analgesics,prostaglandins or the like, that are effective in nanogram and milligramamounts, or the like, to three years or longer for steroids releasedwithin the uterine cavity. Other examples include wherein the amount ofdrug in the reservoir can be 100 to 300 mg of thiopropzate for releasing15 to 30 mg over a 24 hour period; 2 to 10 mg in the reservoir ofpilocarpine for a release of 8 to 25 μg per hour; 2 to 10 mg ofhydrocortisone for releasing 10 μg/hr.; 100 to 200 mg of papaverine inthe reservoir for a release 30 to 75 mg over a 24 hour period; 15 to 25mg of tranylcypromane for a release of 10 to 15 mg as the standard dose;prostaglandins for example PGE₁, PGE₂, PGA₁, PGF₂α in amounts of 0.5 mgto 20 mg for release of intrauterine drug to a mature female mammal atthe rate of 10 ng to 100 ng and the like; for progestational,progestogen, or progesterone the administration in the uterus of 10 to600 μg per day for release for 1 year to 3 years as an anti-fertilityagent in a mature, child-bearing woman weighing 40 kg to 85 kg; an oraldevice administering 300 mg to 600 mg per day of analgesic acetaminophento a 60 to 70 kg adult male; and the like.

Drug-delivery devices of the invention are easily fabricated. When thesystem is in the form of a matrix with drug distributed therethrough,particules of the drug can be mixed with the ethylene-vinyl acetatecopylmer, which can be in the solid, semi-solid, or liquid form at thetime, and distributed therethrough by ballmilling, callendering,stirring, shaking or the like. Where the drug is chemically compatiblewith the monomers used to form the ethylene-vinly acetate copolymer, thedrug particles can be added at this earlier stage and the ethylene-vinylacetate matrix formed in situ. The matrix, however, made and having thedrug particles distributed therethrough, can then be formed to a solidshape by molding, casting, pressing, extruding, drawing or likeprocesses. Thereafter, the matrix can be cross-linked, if desired, forexample, by use of irradiation. Alternatively, the ethylene-vinylacetate copolymer matrix can be formed to the desired shape and placedin a bath of the drug or of a solvent solution of the drug which thendiffuses into the matrix to provide the drug-delivery device. When thedrug-delivery device is a sealed container with walls of ethylene-vinylacetate and the drug in an interior reservoir, the container can befabricated in many ways. Preformed hollow shapes of ethylene-vinylacetate, copolymer such as tubing, can be filled with drug, alone ordispersed in a suitable vehicle, and the ends sealed with plugs or byheat to form the final drug-delivery device. Alternatively, the drug canbe laminated between ethylene-vinyl acetate copolymer sheets which canbe sealed together with adhesive or by heat. Other encapsulation,bonding, and coating techniques conventionally used in the art can beemployed. The ability to shape ethylene-vinyl acetate copolymers intotubes, rods, disks, films, rings and other highly reproducible shapes ofcontrollable composition results in ready fabrication of devices withclosely controlled characteristics and overcomes a significantdisadvantage of previously described devices based on silicone rubberpolymers and other presently known polymers. Other standard procedures,as described in Modern Plastics Encyclopedia, Vol. 46, pages 62 to 70,1969, published by McGraw Hill Co. well known to those skilled in theart can be used to fabricate the drug delivery device of the invention.

In addition to its ease of fabrication, the drug-delivery device of theinvention offers other important advantages. One of these is thatdiffusion of drugs, such as progesterone, through ethylene-vinyl acetatecopolymers proceeds at a lower rate than through silicone rubber andother prior art polymers. This is important because it ensures that therate of drug administration is controlled by diffusion through thepolymer rather than by clearance from the surface of the device. Inaddition, ethylene-vinyl acetate copolymers are not known to absorblipoidal materials at the same rate from the body, as do silicone rubbermembranes and some other polymers, and therefore the characteristics ofthe rate controlling membrane do not vary with time. This permits use ofdrug-delivery devices of the invention for long term therapeuticprograms, for example, in hormone releasing intrauterine devices or inimplantates. Use of silicone rubber and the like as the rate controllingbarrier in such long term dosage forms has not generally beensuccessful. Another added advantage of the present invention is thatethylene-vinyl acetate compolymer seemingly does not give rise tounwanted effects when in contact with biological media.

The reservoir of the drug-delivery device in one embodiment of theinvention is a drug matrix that contacts the inner surface of the drugrelease rate controlling ethylene-vinyl acetate copolymer wall andsupplies drug thereto. The reservoir is comprised of a liquid,semi-solid or solid matrix containing drug, and it is a material that ispermeable to the passage of drug by diffusion. The matrix can be anorganic, inorganic, naturally occurring or synthetic material. Examplesof matrix are gelatin, starches, carbohydrates, Irish moss, hydrophilichydrogels of esters of acrylic acid, modified collagen and likematerials. Also, other commercially available matrixes permeable to thepassage of drug but at a higher rate of passage than through the wall ofthe device are suitable for the reservoir of the device. Representativematrixes are set forth in Remington's Pharmaceutical Science, pages 246to 269, 1338 to 1390 and 1627 to 1979, 1970, published by MackPublishing Company, Easton, Penn.

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, drawings and the accompanying claims.

EXAMPLE 1

Milled crystals of progesterone (60 milligrams) are placed within a tube1.5 cm long, having an inside diameter of 0.125 inch and an outsidediameter of 0.157 inch and formed from an ethylene-vinyl acetatecopolymer essentially insoluble in biological fluids and having a vinylacetate content of 28% by weight and a melt index of 4 grams per tenminutes. The tube ends are heat sealed and the dosage unit used forconception control by attachment to an intrauterine device for example,a Lippe's Loop and inserted into the uterine lumen through the cervix.The device controls fertility by releasing 56 micrograms of progesteroneper day to the uterine cavity of an adult woman.

EXAMPLE 2

Milled crystals of medroxyprogesterone acetate (980 milligrams) areplaced within a tube 23 cm long, having an inside diameter of 0.125 inchand an outside diameter of 0.157 inch and having walls formed ofbiologically acceptable, ethylene-vinyl acetate copolymer having a vinylacetate content of 40% by weight and a melt index of 15 grams per tenminutes. The filled tube is bent to a ring having a circumference of 23cm and the ends heat sealed together. The device is placed in the vaginaat the mouth of the cervix and regulates fertility by release ofmedroxyprogesterone acetate at a slow rate intravaginally for aprolonged period of time.

EXAMPLE 3

Milled crystals of hydrocortisone (800 milligrams) are placed on a filmof ethylene-vinyl acetate copolymer having a thickness of 4 mils, a facesurface area of 4 cm², and formed from a copolymer having a vinylacetate content of 16% by weight and a melt index of 2.5 grams per tenminutes. The hydrocortisone bearing surface of the film is overlaid witha polyethyleneterephthalate sheet of the same dimensions which is heatsealed at its edges to the ethylene-vinyl acetate film. A strip ofpressure-sensitive adhesive (70 parts of 95:5 copolymer of isoamylacrylate and acrylic acid, 5 parts polyvinylethylether with reducedviscosity of 0.3, 1 part castor oil and 4 parts polyethylene-glycol-400)having a width of 2 mm is printed on the face surface of theethylene-vinyl acetate film about the perimeter thereof. When applied tothe skin, hydrocortisone diffuses through the ethylene-vinyl acetatecopolymer sheet, is absorbed by the skin, and is effective to treatvarious dermatitis conditions.

EXAMPLE 4

Milled crystals of diethylstilbestrol (950 milligrams) are mixed with anethylene-vinyl acetate copolymer having a vinyl acetate content of 22%by weight and a melt index of 14 grams per ten minutes. Thedrug-copolymer mixture is ball milled for 20 minutes to provide auniform distribution of the throughout the polymeric carrier.Thereafter, the resulting mixture is shaped in the form of a cylinderhaving a length of 2 cm and a circumference of 0.12 cm. When implantedin the ear of beef cattle, the implantate releases an effective amountof diethylstilbestrol to induce weight gain in the farm animal.

EXAMPLE 5

Pilocarpine oil (200 milligrams) is placed between two films ofethylene-vinyl acetate copolymer each having a thickness of 0.004 inchand formed from an ethylene-vinyl acetate copolymer with a vinyl acetatecontent of 40% by weight and a melt index of 22 grams per ten minutes.Ellipsoidal ocular inserts having a length of 1.3 cm, a width at theirwidest point of 4 mm, and a thickness of 0.5 mm, are heat stamped fromthe assemblage, with each such insert containing 2 milligrams ofpilocarpine. These ocular inserts can be inserted and retained in thecul-de-sac of the conjunctiva between the sclera of the eyeball and thelid, and, when in place, will release a therapeutically effective amountof pilocarpine to control glaucoma to an adult human over a period of 24hours.

EXAMPLE 6

An intrauterine anti-fertility dispensing device is shaped like atriangle with an opening at the vertex of two of the legs. The triangleis formed of a release rate controlling wall permeable to the passage ofan anti-fertility agent and surrounding a reservoir containing a carrierand the agent. The triangle is made as follows: first, a carriercontaining progesterone is injected into a length of biologicallyacceptable, nonerodible, ethylene-vinyl acetate copolymer. The ends ofthe tubing are heat sealed and the tubing is then formed into a triangledevice in a heated mold. The device releases intrauterine 90 to 100micrograms of progesterone per day to a 40 to 80 kg woman.

In summary, it will be readily appreciated that the present inventioncontributes to the art unobvious drug delivery devices having wide andpractical application by the invention's use of ethylene-vinyl acetatecopolymer. As noted supra, it has now been found that ethylene-vinylacetate copolymer can be used for the controlled release of many drugs.In contrast, highly crystalline materials such as polyethylene ormaterials such as partially hydrolyzed polyvinyl acetate having aprofusion of side groups, do not lend themselves to use in likeenvironments. And, while the invention has been described and pointedout in detail and with reference to operative embodiments thereof, itwill be understood that those skilled in the art will appreciate thatvarious changes, modifications, substitutions and omissions can be madewithout departing from the spirit of the invention. It is intended,therefore, that the invention embrace these equivalents within the scopeof the claims which follow.

We claim:
 1. An ocular therapeutic system for the controlled release ofdrug comprising a flexible body formed of a polymeric material permeableto the passage of drug by diffusion and containing a drug capable ofdiffusing through the material at a therapeutically effective rate, thebody shaped, sized and adapted for comfortable insertion and retentionin the cul-de-sac of the conjuctiva between the sclera of the eyeballand the lid to be held in place against the eyeball by the pressure ofthe lid, and wherein said polymeric material comprises an ethylene-vinylacetate copolymer having a vinyl acetate content of about 4 to 80% byweight, and a melt index of about 0.1 to 1000 grams per ten minutes. 2.The ocular system according to claim 1 wherein the drug is an ophthalmicdrug.
 3. The ocular system according to claim 1 wherein the drug ispilocarpine.
 4. An ocular therapeutic system for the controlled releaseof drug comprising a flexible body formed of a polymeric materialpermeable to the passage of drug by diffusion and surrounding a drugcapable of diffusing through the material at a therapeutically effectiverate, the body shaped, sized and adapted for comfortable insertion andretention in the cul-de-sac of the conjunctiva between the sclera of theeyeball and the lid, to be held in place against the eyeball by thepressure of the lid, and wherein said polymeric material comprises anethylene-vinyl acetate copolymer having a vinyl acetate content of about4 to 80% by weight, and a melt index of about 0.1 to 1000 grams per tenminutes.
 5. The ocular system according to claim 4 wherein the body is acontainer with drug contained therein.
 6. The ocular system according toclaim 4 wherein the drug is an ophthalmic drug.
 7. The ocular systemaccording to claim 4 wherein the drug is pilocarpine.
 8. An oculartherapeutic system for the controlled and continuous administration ofdrug to the eye of a warm blooded animal comprising a body formed of apolymeric material permeable to the passage of drug by diffusion andsurrounding a drug capable of diffusing through the material at atherapeutically effective rate, the body shaped, adapted and sized witha length of 4 to 20 mm, a width of 0.1 to 12 mm and a thickness of 0.1to 4 mm for insertion and retention in the eye, and wherein the materialcomprises an ethylene-vinyl acetate copolymer having a vinyl acetatecontent of about 4 to 80% by weight and melt index of about 0.1 to 1000grams per ten minutes, with the copolymer when the system is in the eyeadministering drug to the eye at a controlled rate over a prolongedperiod of time.
 9. The ocular system according to claim 8 wherein thebody is a container and the drug is contained therein.
 10. The ocularsystem according to claim 8 wherein the copolymer surrounds a reservoircontaining an ophthalmic drug.
 11. The ocular system according to claim8 wherein the drug is pilocarpine.
 12. An ocular therapeutic system forthe controlled administration of drug to the eye comprising a bodyformed of a drug release rate controlling ethylene-vinyl acetatecopolymer permeable to the passage of drug by diffusion and containing adosage amount of a drug capable of diffusing through the copolymer, saidbody shaped, adapted and sized for comfortable insertion and placementin the eye, and wherein the body when in the eye administers atherapeutically effective amount of drug by the drug dissolving in andpassing through the copolymer at a controlled rate over a prolongedperiod of time.
 13. The ocular system according to claim 12 wherein thecopolymer has a vinyl acetate content of 4 to 50% by weight, a meltindex of 0.5 to 250 grams per 10 minutes, a density of 0.920 to 0.980,and a frequency of acetoxy groups on the ethylene backbone of 1/150 to1/8.
 14. The ocular system according to claim 12 wherein the drug is anophthalmic drug.
 15. The ocular system according to claim 12 wherein thedrug is pilocarpine.
 16. An ocular therapeutic system for administeringdrug to the eye comprising a body shaped and sized for comfortableinsertion and retention in the eye, the body formed of a drug releaserate controlling ethylene-vinyl acetate copolymer having a vinyl acetatecontent of 4 to 80% by weight, permeable to the passage of drug bydiffusion and surrounding a drug capable of diffusing therethrough, andwherein said body when in the eye administers a therapeuticallyeffective amount of drug by passage through the copolymer at acontrolled rate over a prolonged period of time.
 17. The ocular systemfor administering drug to the eye according to claim 16 wherein thecopolymer has a melt index of 0.1 to 1000 grams per 10 minutes and thedrug is an ophthalmic drug.
 18. The ocular system according to claim 16wherein the body is a container with the drug contained in the reservoirthereof.
 19. The ocular system according to claim 16 wherein the drug ispilocarpine.